1

Written Testimony of Ashish K. Jha, MD, MPH

Professor of Health Services, Policy, and Practice

Dean of the School of Public Health

Brown University

Testimony to the Committee on Homeland Security and Governmental Affairs

November 19, 2020

2

Introduction In the last week, two major pharmaceutical companies announced the preliminary results of their

vaccine trials, promising a potential end to the pandemic. At the same time, we are entering the

worst phase of the pandemic, with infections spiking across the nation, hospitalizations at an all-

time high,1 and deaths climbing. Until vaccines become widely available, therapeutic treatments

for COVID-19 will continue to play an important role in reducing deaths among those who are

infected. Researchers are continuing to gather evidence on the use, safety, and efficacy of different

treatments in clinical trials, including several testing outpatient treatments. The early evidence

from some of these trials is promising, while other treatments have now been discredited through

robust Randomized Controlled Trials (RCTs). I will outline four major categories of outpatient

therapies and the evidence for their effectiveness before discussing the importance of adhering to

established scientific approaches in evaluating these treatments, and other coronavirus

countermeasures.

Early Outpatient Treatments

A key goal for therapeutics for SARS-CoV2 has been early outpatient therapy. Early intervention,

ideally with a treatment that prevents severe complications of the disease, can prevent

hospitalizations, disability, and death. By treating people at home or in their physicians’ offices,

we can avoid maxing out hospital capacity at a time when our medical resources are stretched to

the limit.

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Four classes of COVID-19 therapies have been investigated for use in the treatment of early

disease in the outpatient setting: 1) antivirals; 2) monoclonal antibodies; 3) convalescent plasma;

and 4) hydroxychloroquine.

Dexamethasone (a steroid) has been shown to be highly effective in clinical trials, but only in

people with advanced disease (those with low oxygen levels or hypoxemia); giving this drug early

in the disease course appears to increase mortality, not lower it. Therefore, it is likely not suitable

for outpatient therapy except in very rare circumstances where hospital services may not be

available.

I. Antivirals

Remdesivir has had a mixed track record, with some clinical trials finding benefit and others none.

A Randomized Controlled Trial in the New England Journal of Medicine found treating patients

with remdesivir shortened hospitalization times and improved patient outcomes. However, the

WHO Solidarity Trials, in their interim report, found no effects of remdesivir on improving

mortality or recovery.2, 3 Clinical trials in early outpatient settings are ongoing, and inconclusive.

Gilead is running a Phase III trial of around 1200 outpatients, to estimate the effectiveness of

remdesivir.4 They have also begun Phase I/II trials for inhaled remdesivir as opposed to

intravenous doses.5 Last month, Atrium Health initiated three outpatient trials to test remdesivir.6

New antivirals are also being developed for mild outpatient cases, including MK-4482 from Merck

and Synairgen’s SNG001. These have been facilitated by Operation Warp Speed and the NIH’s

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ACTIV-2 (Adaptive Platforms Treatment Trial for Outpatients with COVID-19) trials.7 Although

we are in the first stages of these clinical trials, the preliminary data seems promising.

Merck’s MK-4482 antiviral is still in Phase IIb trials, with interim results due early next year.8 But

more evidence has been released for SNG001 - an antiviral originally developed to treat chronic

obstructive pulmonary disease. The Lancet recently published results from a Randomized

Controlled Trial (RCT) focusing on hospitalized patients who were not receiving intensive care or

ventilation.9 The researchers found a strong improvement in clinical status for those who received

the treatment, an effect that became more pronounced later in the disease course. Another trial is

underway for both hospitalized and non-hospitalized high-risk patients, but we do not yet have

enough evidence in outpatient settings to claim efficacy.10

Camostat Mesylate, a protease inhibitor, has been shown to reduce levels of TMPRSS2, a serine

protease highly associated with the spread of infectious diseases.11 Camostat has proved effective

in combating the original SARS virus, SARS-CoV, but has not yet been tested in patients with

SARS-CoV-2.12 Clinical trials are ongoing, but some reports suggest Camostat Mesylate, and its

cousin Nafamostat Mesylate, may be effective in inhibiting the spread of COVID-19 in human

lungs.13

II. Monoclonal Antibodies

Alongside antivirals, pharmaceutical companies have been working to develop effective

monoclonal antibodies, which work to target the virus and inhibit its spread. The first data from

Regeneron’s REGN-2 antibody in late September covered 275 patients.14 The next round of data

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was released in late October and included an additional 524 patients from Phase II/III.15 Patients

were randomized to receive either a high dosage, low dosage, or placebo. Only non-hospitalized,

healthy individuals were eligible for the trials. The preliminary results suggest viral loads, medical

visits, and time to alleviate symptoms were all reduced compared to the placebo. On average,

treated patients had a more than 10-fold reduction in viral loads.15 The largest benefits were

reported in patients who had not yet mounted their own immune response, and those classified as

highest risk. Regeneron has submitted their data to the FDA for Emergency Use Authorization

(EUA) consideration and have committed to continuing their trials. The UK Recovery project has

also added REGN-2 as a treatment option for participants, though preliminary data is still being

gathered.16

Eli Lilly’s antibody has also shown positive results in the same patient population. An interim

analysis of the ongoing Phase II clinical trial (BLAZE-1) found patients who received the Ly-

CoV555 antibody had slightly lower severity of symptoms, and lower hospitalization rates

compared with the placebo.17 The medium dosage resulted in a significant reduction in viral load,

and patients did not report adverse effects. Given the positive results demonstrated through this

randomized-controlled trial, the FDA recently issued an EUA for Ly-CoV555 for treatment of

mild to moderate COVID-19 cases in patients who are at high risk of progressing to severe illness

or hospitalization.18

III. Convalescent Plasma

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Naturally occurring antibodies are also found in convalescent plasma, which has already been used

as a therapy for COVID-19. Unfortunately, the results from convalescent plasma trials have not

been nearly as encouraging.

Convalescent plasma, a treatment in which blood from recovered COVID-19 patients is transfused

into actively infected individuals, was first approved through an EUA on August 23, 2020. The

observational data backing the EUA for convalescent plasma showed that patients who received

the therapy earlier in the disease course demonstrated a lower 7-day mortality than those receiving

the therapy later in the disease course.19 However, in the absence of an RCT, it is impossible to

disentangle whether these results indicate a benefit of treatment with the drug early or a harm of

the drug later on. In the first RCT of convalescent plasma, the therapy did not significantly reduce

the time to clinical improvement within 28 days.20 Furthermore, an RCT conducted in the

Netherlands demonstrated no difference in mortality, length of hospital stay, or disease severity at

Day 15 between those who received convalescent plasma therapy and those receiving standard of

care.21 Both of these trials were terminated early and therefore, their results must be interpreted

with caution. But a more recent RCT examining convalescent plasma therapy failed to demonstrate

a statistically significant reduction in disease progression or mortality.22 The study found that 15%

of patients who completed the therapy died, compared with 14% of those who received usual care.

The trial did demonstrate some benefits, such as relief from shortness of breath and an increased

likelihood of testing negative after 7 days, but these benefits must be interpreted with caution,

given the non-blinded nature of the study. Further, the administration of convalescent plasma

treatment does not come without risks. A commentary in the British Medical Journal noted the risk

of convalescent plasma included blood clots, among other common complications.23 In fact,

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convalescent plasma poses a number of other potential risks to patients, such as transfusion-related

risks (to both those receiving convalescent plasma treatments and comparators receiving regular

plasma during clinical trials) and allergy or anaphylaxis.24 While this therapy has not yet been

testing in the outpatient setting, a number of clinical trials of convalescent plasma for outpatients

are currently underway.25

IV. Hydroxychloroquine

Hydroxychloroquine was the first therapy that received an EUA for COVID-19. The evidence

cited by President Trump and the FDA centered around a small trial of 26 COVID-positive patients

run by French scientist Didier Raoult. After receiving six daily doses of hydroxychloroquine, 70%

of treated patients returned a negative test. However, following the publication of the results, many

European scientists questioned the trial procedures, including the small sample and biases in

patient selection. Raoult’s findings were soon discredited.26

Today, the consensus in the scientific community, based on overwhelming evidence, is that

hydroxychloroquine provides no benefits in treating COVID-19, and may produce significant

harms. Results from an RCT published in the New England Journal of Medicine found

hydroxychloroquine had no effect on the chances of becoming infected after exposure.27 The UK

Recovery Trials, which prescribed hydroxychloroquine to hospitalized individuals, reported

higher mortality for COVID patients for those in the treatment arm.28 Interim results from the

WHO Solidarity Trials also reported no significant difference in the mortality for those assigned

to hydroxychloroquine as opposed to a placebo.3 The TEACH clinical trials found similar effects,

concluding diagnosed COVID patients who were assigned hydroxychloroquine as opposed to a

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placebo did not perform better across clinical outcomes, and had longer hospital stays.29 Another

systematic review of 29 papers found hydroxychloroquine alone did not reduce mortality, and in

combination with another commonly used therapeutic, azithromycin, actually increased deaths.30

Yet another study analyzed a WHO database of over 21 million records across 130 countries and

found strong evidence of a disproportionate share of reported adverse reactions in patients taking

hydroxychloroquine, either alone or in combination with azithromycin.31 The Veterans

Administration ran a retrospective analysis of veterans’ electronic health records, and concluded

that hydroxychloroquine, alone or with azithromycin, did not reduce ventilations or overall

mortality, but were instead linked to longer hospital stays.32 The best evidence suggests that

hydroxychloroquine is ineffective in improving COVID-19 outcomes. Similar to initial

observations suggesting hydroxychloroquine would be effective against COVID-19 throughout

the course of illness, some now suggest that there is a benefit to using the drug very early on, in

the first 5-10 days after symptom onset.33 However, there is no evidence to support this contention

and better data are clearly needed.

Not only has hydroxychloroquine demonstrated minimal to no benefit in treating COVID-19, but

it also poses substantial risks to patients. Hydroxychloroquine, an aminoquinoline derivative, has

a very narrow therapeutic range. Only a small range of doses can be tolerated without leading to

toxicity.34 While hydroxychloroquine toxicity is not very common, its use for COVID-19 requires

a higher dosage than normally employed, and therefore, raises concern of greater side-effects and

toxicity. In April of 2020, we saw a 93% increase in hydroxychloroquine and chloroquine

exposures reported to the U.S. Poison Control Centers, compared with April of 2019, presumably

due to the large number of people taking hydroxychloroquine for COVID-19.

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The EUA Approval Process

The central question in evaluating new therapies is whether FDA should approve Emergency Use

Authorizations (EUAs) to fast track the deployment of these drugs. EUAs permit the usage of

unapproved medical products to diagnose, treat, or prevent deadly diseases or conditions. They are

reserved for patients with life-threatening conditions and chronic illnesses. In order to approve

EUAs, the FDA asks a series of linked questions. Do the potential benefits outweigh the risk? Will

the product actually be effective? Are we confident we can follow up with patients and track their

long-term health outcomes? And do we have sufficient data to make a decision?35, 36 Because of

the immense impact of an EUA, the decision process must take into account evidence from each

phase of clinical trials.

Many of the preliminary findings from early outpatient therapeutics are promising, especially for

antivirals and monoclonal antibodies. And the data on monoclonal antibodies, especially from

Lilly, appears to be enough to issue an EUA. But we must remain vigilant about not giving in to

the temptation to issue EUAs without clear evidence. Our lapse in judgement during the first stage

of this pandemic has provided us with a valuable lesson: we need to let science do its job. We must

not authorize a treatment for widespread use before its efficacy and safety are clear. We cannot set

arbitrary timelines for the scientific process to deliver us results. And we absolutely cannot

politicize this process.

Both hydroxychloroquine and convalescent plasma were lauded as “miracle cures” but have

recently been proven ineffective, and potentially dangerous. In both cases, the politicization of the

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scientific process pressured the FDA into prematurely issuing EUAs, despite lack of adequate

evidence on efficacy or safety. Hydroxychloroquine is still embraced by many to this day. As an

unpatented drug, it is relatively affordable and was widely available, making it a popular option

for treatment. Many patients took hydroxychloroquine in the early months of the pandemic. After

all, nothing else was on hand, and it was effective against other diseases. The first double-blind

clinical trials of the drug were approved with a rapid turnaround. Yet before they could even begin,

a series of preprints asserting the efficacy of hydroxychloroquine in treating COVID-19 led to a

social media storm. Despite warnings from public health officials on the lack of evidence linking

hydroxychloroquine to stronger patient outcomes, the FDA approved an EUA less than two weeks

later, on March 27th.37

A very similar approach was taken to justify the use of convalescent plasma to treat COVID

patients. The FDA processed an EUA in late August, during a televised announcement by the

Trump administration. The Commissioner of the FDA, Dr. Stephen Hahn, and President Trump

both exaggerated the benefits of plasma despite a lack of evidence on its ability to temper infections

or reduce mortality. Just nine days later, the NIH countered the FDA, stating there was not enough

evidence for an EUA to have been approved.38

The willingness to approve these drugs, despite clear concerns from the scientific community,

seemed to stem from political considerations and the election timeline, in keeping with Dr. Stephen

Hahn’s tweets and President Trump’s promises of a vaccine before the election. These comments

suggested that the President’s reelection campaign was more important than patient safety, with

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the result that 72% of Republicans, and 82% of Democrats were concerned that politics would

influence vaccine approvals.39

The risks of prematurely issuing an EUA for a therapy extend beyond direct patient harm. Such

approvals present additional barriers to conducting randomized-controlled trials and generating

rigorous scientific evidence. Once a drug has been advertised as effective through an EUA, patients

become increasingly unwilling to receive a placebo treatment and physicians increasingly hesitant

to prescribe one, making it more challenging to enroll participants in RCTs.40

Fueled by misinformation and the politicization of public health, many Americans have come to

see these unproven therapeutics as cures. Politicization breeds misinformation, and misinformation

fuels politicization. Disagreements between our country’s leading health agencies on safety and

efficacy of previously approved drugs undermines trust in public health measures across the board.

The Harms of Uninformed Policy Decisions

Deploying novel therapeutics and treatments without robust and rigorous scientific evidence can

threaten the health and safety of Americans, and ultimately hinder our nation’s ability to bring this

pandemic under control. This risk is well established; historically, we have witnessed the harms

of prematurely electing an unproven therapy. During the 2003 SARS coronavirus outbreak, for

example, physicians began to treat patients with a combination of steroids and high-dose ribavirin,

despite thin evidence for the drug’s use with coronavirus and many serious side effects. These

same mistakes were repeated during the 2014-16 Ebola outbreak, when physicians utilized novel

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therapies such as ZMapp, a triple monoclonal antibody cocktail, which was ultimately deemed

ineffective through RCTs.41

Premature approval of EUAs for experimental treatments has likewise harmed patient health and

safety during the COVID-19 pandemic. The approval of convalescent plasma relied on

retrospective, indirect evaluations rather than randomized-controlled trials, the gold standard

needed to demonstrate safety and efficacy. Hydroxychloroquine demonstrated even less scientific

promise than convalescent plasma but was highly promoted by the President. Despite a lack of

evidence, an EUA was issued in late March. The results from later clinical trials were clear:

hydroxychloroquine did not work. The FDA was forced to revoke its EUA, and clinical trials were

paused. In many ways, our approach to hydroxychloroquine and convalescent plasma have been

prime examples of what not to do in a public health crisis.

In April, about one month after President Trump praised hydroxychloroquine and falsely

advertised its benefits, the price of the drug skyrocketed, with a 100-gram container of

hydroxychloroquine sulfate increasing in price by about 350%.42 Following President Trump’s

statements touting the drug, U.S. pharmacies saw a 46-fold spike in prescriptions for

hydroxychloroquine, resulting in shortages across the nation and patients unable to obtain their

usual prescriptions for other chronic conditions.41, 43 This same price increase followed the

President’s use of dexamethasone, which demonstrated a price increase of 137% in recent

months.44 Hydroxychloroquine can be an effective therapy for individuals with lupus and

rheumatoid arthritis while dexamethasone is critical in treating various autoimmune diseases.

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Ultimately, overstating the benefits of these drugs in treating COVID-19 made this medication less

accessible for individuals living with diseases for which the benefits are well established.

While the unprecedented circumstances of this global pandemic justifies urgency, and a

willingness to try out new treatments that demonstrate potential, these tradeoffs must be evaluated

carefully. Some have justified the rapid approval of these experimental treatments with the Right

to Try Act, a law that enables patients with life-threatening conditions to access certain unapproved

or experimental treatments. And while there is a time and a place for this type of legislation, the

COVID-19 pandemic is certainly not that. The Right to Try is generally employed in desperate

situations, for conditions that offer no tried-and-true alternative. But we do have other options

when it comes to COVID-19, including treatments and therapeutics that have demonstrated some

success in randomized-controlled trials and are shown to help the most critically ill patients, such

as remdesivir and dexamethasone.

It is of the utmost importance that our federal agencies, the gold standard for our nation and the

world at large, are respected and left to do their work in peace. And more importantly, the process

of review must be transparent, unbiased, and rigorous, restoring our nation’s faith in the scientific

method before vaccines become widely available in 2021. Leaders of federal agencies also need

to be well versed in their own work, so that they don’t need to retract erroneous statements and

issue apologies for inaccuracies later.

Conclusion

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We have a range of potential therapies for COVID-19, including many that appear promising from

the preliminary data. But for the good of our patients, we must avoid the temptation to short-circuit

the scientific process of gathering and analyzing data, even in the midst of this pandemic. Short-

circuiting the scientific process risks a number of serious harms to patients, in both inpatient and

outpatient settings.

First, therapeutics that are not adequately vetted and studied can cause direct medical harm to some

patients, as seems to be the case with hydroxychloroquine, which can precipitate cardiac

arrhythmia, or even poisoning. Second, encouraging the off-label or unauthorized use of

inadequately vetted therapeutics through EUAs or other public communications, can radically

distort the market, raising prices and causing shortages that affect patients who need drugs to treat

labelled conditions. Third, encouraging use of treatments prematurely can gravely impair efforts

to gather precisely the data we require to understand if and when to use candidate therapies.

Widespread, unregulated use of hydroxychloroquine significantly delayed our ability to assess its

efficacy in clinical trials. Likewise, the unstructured and unregulated deployment of convalescent

plasma muddied the evidence as to the efficacy of the treatment, including whether it is effective

early or late in the course of disease, by limiting the number of patients who could be recruited to

study trials and limiting the availability of the treatment itself. Closely related, studying a candidate

treatment carries a significant opportunity cost. The effort to expand treatments like convalescent

plasma is extremely demanding, requiring the identification of recruitment of volunteers, plasma

collection and purification, even before it is administered to patients. We have limited resources,

and no time to spare. Investing heavily in such treatments in the absence of robust evidence of

efficacy impedes efforts to identify and test other potential treatments.

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As a physician, I need to know six key facts about any treatment before I take responsibility for

administering it to my patients:

1. In which patients is the treatment effective?

2. How effective is the treatment?

3. What are comparable alternative treatments?

4. At what point in the disease course is it effective?

5. When should treatment be discontinued?

6. What are the major side effects of the treatment?

At present, we simply don’t have enough evidence to answer many of these questions for

hydroxychloroquine or convalescent plasma. The answers can only come from well-designed

RCTs. The scientific community has made a superhuman effort to identify and test novel

therapeutics, working at unprecedented speed. If we short-circuit these processes, we risk

undermining all of our work, to the detriment of patients. Clinical trials can be done quickly with

resources and effort and history has shown us that they are the only way to have confidence in our

treatment options. Going forward, the federal government must handle the EUA process in an

apolitical, transparent, and scientifically-grounded manner.

We must protect the health and safety of patients by relying on science and moving things quickly

by investing more, not cutting corners. Only by following established standards of evidence can

we ensure that experimental treatments are not harmful to patients, either directly through side

effects or indirectly through the exclusion of individuals with other chronic conditions.

16

The death toll of this pandemic is unprecedented, and it comes as no surprise that many of us -

physicians, patients, and policymakers - are desperate for solutions, and are tempted to resort to

desperate measures. But it is precisely during a pandemic that we need science most - when the

risk of sacrificing that scientific rigor is greatest. Recent announcements suggest that we will be

able to deploy highly effective vaccines in a few months, thanks to scrupulous adherence to

scientific principles by those responsible for running and evaluating vaccine candidates. To protect

those who will be infected before a vaccine is widely available, we must use the same rigor in

evaluating COVID-19 treatments.

17

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